Project Summary The main objective of the proposed research is to develop a wearable transcranial focused ultrasound (tFUS) environment that reversibly modulates (either elicits or suppresses) region-specific neural activities of the brain. We will develop an image-guided sonication system, capable of delivering highly- focused (roughly the size of a rice grain) acoustic energy to the desired location of the sheep brain through the intact skull, and integrate it with the capability for evaluating the degree of modulation using behavioral (motion detection) and electrophysiological recordings (electroencephalography and electromyography) as well as functional magnetic resonance imaging (fMRI). We will examine sonication parameters and their corresponding modulatory effects on the cortical and thalamic areas of the brain based on closed-loop monitoring of the electrophysiological data. The tFUS transducer will be developed in the form of a wearable headgear that can be applied among unanesthetized, freely-moving sheep to modulate the function of primary motor area and its thalamic projection (ventrolateral nucleus). To probe the safety of the method, immunohistological analysis examining biological effects of the sonication will be performed at variable time points, covering acute, delayed, and long-term periods after the sonication. The ability to non-invasively modulate a specific brain area, with exquisite depth penetration and spatial resolution, would provide an unprecedented opportunity in the study of causal relations between brain activity and behavior. The success of this study will result in the exploration of novel potential therapeutic applications of tFUS for numerous neurological and psychiatric disorders.